A member of the Rare Diseases Clinical Research Network (RDCRN), the North American Mitochondrial Disease Consortium (NAMDC) has established a network of 18 clinical centers to improve the diagnosis, establish the natural history, and investigate treatment of mitochondrial diseases. Mitochondrial diseases are clinically and genetically heterogeneous due to primary mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Only through a consortium, acting in close collaboration with the patient advocacy groups. United Mitochondrial Disease Foundation (UMDF) and Muscular Dystrophy Association, can we address these complex diseases. With support of an NIH American Recovery and Recovery Act (ARRA) grant and 2 years of a U54 award, NAMDC has already produced a powerful Clinical Registry/Clinical Longitudinal Study with over 425 enrolled patients, a Biorespository, a website for education and recruitment of patients, and mitochondrial disease Research Diagnostic Criteria, which are the foundation for additional clinical research studies. From this firm base, productive patient-oriented projects have already sprouted including 3 natural history studies (mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), Alpers syndrome, and Pearson syndrome, a pilot study of ultra-high field nuclear magnetic resonance to assess metabolites in muscle and brain of patients with mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), as well as extensive preliminary work (including a successful FDA IND application) setting the stage for an innovative adaptive safety study of allogeneic hematopoietic stem cell transplantation (AHSCT) for MNGIE. The NAMDC training program has been established to train the next generation of clinician investigators. Additional work is required to reap the rewards of the labor invested in this consortium. In this application, we propose to expand the NAMDC Clinical Registry/Longitudinal Study and Biorepository; to apply and refine the Research Diagnostic Criteria; to continue on-going natural history studies; to complete the MNGIE AHSCT safety study; to launch a natural history and advanced genetics study of pyruvate dehydrogenase complex deficiency; to initiate new pilot studies including a phase I study of citrulline therapy fr MELAS; to continue the NAMDC clinical fellowship training program; and to develop new lines of research and collaborations including investigation of use of nutritional supplements among mitochondrial disease patients and close collaborations with the mitochondrial disease sequence data resource (MSeqDR) consortium.